Implementing Outcomes‑Based Managed Entry Agreements for Rare Disease Treatments: Nusinersen and Tisagenlecleucel

(1)

Vol.:(0123456789) https://doi.org/10.1007/s40273-021-01050-5

ORIGINAL RESEARCH ARTICLE

Implementing Outcomes‑Based Managed Entry Agreements for Rare Disease Treatments: Nusinersen and Tisagenlecleucel

Karen M. Facey¹ · Jaime Espin^2,3,4 · Emma Kent⁵ · Angèl Link⁶ · Elena Nicod⁷ · Aisling O’Leary⁸ · Entela Xoxi⁹ · Inneke van de Vijver¹⁰ · Anna Zaremba¹¹ · Tatyana Benisheva¹² · Andrius Vagoras¹³ · Sheela Upadhyaya⁵

Accepted: 1 June 2021 / Published online: 7 July 2021

Abstract

Background and Objective Enthusiasm for the use of outcomes-based managed entry agreements (OBMEAs) to manage uncertainties apparent at the time of appraisal/pricing and reimbursement of new medicines has waned over the past decade, as challenges in establishment, implementation and re-appraisal have been identified. With the recent advent of innovative treatments for rare diseases that have uncertainties in the clinical evidence base, but which could meet a high unmet need, there has been renewed interest in the potential of OBMEAs. The objective of this research was to review the implementation of OBMEAs for two case studies across countries in the European Union, Australia and Canada, to identify good practices that could inform development of tools to support implementation of OBMEAs.

Methods To investigate how OBMEAs are being implemented with rare disease treatments, we collected information from health technology assessment/payer experts in countries that had implemented OBMEAs for either nusinersen in spinal muscular atrophy or tisagenlecleucel in two cancer indications. Operational characteristics of the OBMEAs that were publicly available were documented. Then, the experts discussed issues in implementing these OBMEAs and specific approaches taken to overcome challenges.

Results The OBMEAs identified were based on individual outcomes to ensure appropriate use, manage continuation of treatment and in two cases linked to payment schedules, or they were population based, coverage with evidence development.

For nusinersen, population-based OBMEAs are documented in Belgium, England and the Netherlands and individual-based schemes in Bulgaria, Ireland, Italy and Lithuania. For tisagenlecleucel, there were population-based schemes in Australia, Belgium, England and France and individual-based schemes in Italy and Spain. Comparison of the OBMEA constructs showed some clear published frameworks and clarity of the uncertainties to be addressed that were similar across countries. Agreements were generally made between the marketing authorisation holder and the payer with involvement of expert physicians. Only England and the Netherlands involved patients. Italy used its long-established, national, web-based, treatment-specific data collection system linked to reimbursement and Spain has just developed such a national treatment registry system. Other countries relied on a variety of data collection systems (including clinical registries) and administrative data. Durations of agreements varied for these treatments as did processes for interim reporting. The processes to ensure data quality, completeness and sufficiency for re-analysis after coverage with evidence development were not always clear, neither were analysis plans.

Conclusions These case studies have shown that important information about the constructs of OBMEAs for rare disease treatments are publicly available, and for some jurisdictions, interim reports of progress. Outcomes-based managed entry agreements can play an important role not only in reimbursement, but also in treatment optimisation. However, they are complex to implement and should be the exception and not the rule. More recent OBMEAs have developed document cov- enants among stakeholders or electronic systems to provide assurances about data sufficiency. For coverage with evidence development, there is an opportunity for greater collaboration among jurisdictions to share processes, develop common data collection agreements, and share interim and final reports. The establishment of an international public portal to host such reports would be particularly valuable for rare disease treatments.

Extended author information available on the last page of the article

(2)

Key Points for Decision Makers

Outcomes-based managed entry agreements can in some circumstances help resolve uncertainties relating to the value and optimal use of a rare disease treatment, but they should be supported by a covenant agreed by all stakeholders providing assurance that all necessary actions will be taken to ensure that the data collected will be sufficient for decision making.

When used, outcomes-based managed entry agreement constructs for data collection and reports of clinical results should be published and shared to enable agreement of core data across jurisdictions, data aggregation and to support health system learnings.

An international public repository for outcomes-based managed entry agreement reports akin to the HTA data- base hosted by the International Network of Agencies for Health Technology Assessment would be valuable.

1 Background

Because of the difficulties associated with clinical research in rare diseases, treatments often come to market with a small evidence base involving uncontrolled or small ran- domised controlled trials of short duration, studying outcomes that may not clearly demonstrate patient benefit [1].

This leads to a range of uncertainties relating to the population appropriate for reimbursement, and to the determina- tion of clinical and cost effectiveness. Alongside this, rare disease treatments are often associated with high prices, which challenge standard willingness-to-pay thresholds and raise concerns about budget impact, even after negotiation of financial/commercial agreements. Some countries have special appraisal and reimbursement mechanisms that allow flexibility in evaluation of rare disease treatments [2], such as leniency in critical assessment/review of evidence, flexibility in base-case assumptions for economic modelling and broader consideration of value. Despite these adapted approaches, some treatments for which substantial clinical benefit or large gains in quality-adjusted life-years are esti- mated are still associated with major uncertainties, which means they cannot be recommended for use or full reimbursement in a health system. Alongside this, the high unmet need, childhood onset and severity of many rare diseases means there is often strong clinical, patient/parent and politi- cal lobbying to provide access to such rare disease treatments. In these situations, one solution to access could be

an outcomes-based managed entry agreement (OBMEA)¹ that seeks to manage the clinical and financial uncertainties [3, 4].

Outcomes-based managed entry agreements can be used with any form of health technology and occur at two levels for a range of purposes including resolution of uncertainties in clinical evidence, management of budget impact, and improved understanding of real-life and long-term effectiveness to optimise care:

Individual: ensuring only eligible patients receive treatment, sometimes with assessment of outcomes to determine treatment continuation (appropriate use) or linked to payment schemes (paying only if response achieved or refund if response not achieved)

Population: using coverage with evidence devel- opment (CED)/post-licensing evidence generation as a conditional coverage mechanism post-health technology assessment (HTA)/reimbursement that requires evidence collection to inform re-appraisal or pricing and reimbursement re-negotiations

However, even with prevalent conditions, implementation of OBMEAs has been found to be challenging [5, 6] owing to administrative burdens on health providers/

payers and for population-based schemes, the insuffi- ciency of data to inform re-appraisal and funding of data collection [7]. Pricing and reimbursement processes are the responsibility of the Ministry of Health nationally and/or a payer, which may have a “jurisdiction” that is national, relates to a region in the country or to a population covered by the health plan. Furthermore, these OBMEAs must be agreed alongside confidential commercial arrangements, thus the constructs of the OBMEAs are often kept confidential or published in local languages that have made sharing difficult. As a consequence, different agreements arise for the same treatment in different jurisdictions. This represents a challenge for the marketing authorisation holder (company/health technology sponsor), but for rare diseases this is also an important inefficiency as sharing of outcomes data across jurisdictions could create more robust evidence for re-appraisal [8, 9].

Work Package (WP) 10 of the European Commission- funded H2020 IMPACT HTA project has undertaken research to develop an appraisal framework suitable for rare disease treatments that includes consideration of when and how to implement OBMEAs. For this, IMPACT HTA WP10 drew on the European Commission-funded H2020 COMED

1 Including performance-based risk sharing schemes/agreements and coverage/post-licensing/access with evidence/data development/generation/collection.

(3)

project. The COMED systematic review of CED schemes [10] identified a range of challenges, many of which seemed transferable to rare disease treatments. We categorised these into issues relating to:

• Establishment (including purpose, stakeholder responsi- bilities, agreement on eligibility and continuation criteria, outcomes to be studied)

• Implementation (including research protocol, data collection infrastructure, monitoring to improve data quality and completeness, amendment processes, feedback mechanisms for physicians and patients, resourcing, ethi- cal issues)

• Re-appraisal (including ability to implement a revised reimbursement decision).

Reckers-Droog et al. [10] suggested that future research should seek to deepen understanding of the challenges of OBMEAs for different health technologies and consider impacts for all stakeholders including clinicians and patients.

Hence, IMPACT HTA WP10 organised workshops with all stakeholders involved in National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies (HST) OBMEAs (called managed access agreements).

These OBMEAs gather data from a variety of health system sources for treatments of ultra-rare conditions that are provided in a national specialised service in NHS England.

Then EX undertook a desktop review of the national web- based registry system of the Italian Medicines Agency, AIFA [11]. This in-depth evaluation of all AIFA registries over a 15-year period identified 88 registries for rare disease indications and explored their form, evolution and impact.

This work from England and Italy showed some differences in approaches to OBMEAs, but with a commonality of issues in relation to clinician (physicians and pharmacists) burden of data entry and assessment. As a result, it was decided to review the implementation of OBMEAs for two specific rare disease treatments across a much broader range of countries. The purpose was to explore how different health systems had established and implemented both individual and population-based OBMEAs and identify good practices that could inform development of tools to support OBMEAs for rare disease treatments.

2 Methods

Given emerging findings in other parts of IMPACT HTA WP10 research, two different treatments designated as orphan medicinal products (OMP) by the European Medi- cines Agency were chosen as case studies: nusinersen and tisagenlecleucel. Nusinersen (Spinraza^®) has European Union regulatory authorisation for 5q spinal muscular

atrophy (SMA) and is administered as an intrathecal injection with four loading doses in the first 2 months and then a maintenance dose every 4 months thereafter, continued dependent on response. Tisagenlecleucel (Kymriah^®) is a one-off CAR-T therapy with European Union regulatory authorisation for patients aged up to 25 years with refractory/relapsed B-cell acute lymphoblastic leukaemia or adults with relapsed/refractory diffuse large B-cell lymphoma.

These provide contrasting cases of: non-cancer vs cancer;

ongoing vs one-off treatment; babies/adults vs adolescents/

adults; antisense oligonucleotide vs advanced therapeutic medicinal products; different HTA/reimbursement routes within organisations.

With a good understanding of the processes to undertake OBMEAs at NICE and AIFA, a template was developed to capture relevant information about OBMEAs in other jurisdictions. In February 2020, the template was sent to HTA/payer/academic experts in each country in the Euro- pean Union, European Economic Area, Canada, Australia and New Zealand that we had worked with in the docu- mentation of appraisal processes in another workstream of IMPACT HTA WP10. They were asked to complete the templates using publicly available information. We sent several reminder e-mails over the coming months, but this coincided with the emergence of the COVID-19 pandemic and thus we were sensitive to health system pressures. Therefore, we con- tacted a market access expert from each marketing authorisation holder to identify the countries where their products had been reimbursed and those that were likely to have an OBMEA and targeted repeated follow-ups to these countries.

The completed templates were reviewed by KF to clarify entries and reduce duplication. Each revised table was validated by the relevant HTA expert. The HTA/payer/academic experts (authors) that contributed detailed information were invited to two virtual workshops in autumn 2020 to discuss their entries in the revised tables, differences in processes, new initiatives that had been implemented to overcome previous challenges with OBMEAs and the potential for future collaboration in relation to OBMEAs for rare disease treatments.

3 Results

3.1 Data Returns 3.1.1 Nusinersen

In the data collection phase in summer 2020, it was recog- nised that the following countries had not authorised/reimbursed nusinersen or were unlikely to have an OBMEA:

Croatia, Denmark, Estonia, Greece, Iceland, Liechtenstein, Luxembourg, Malta, New Zealand, Romania and Slovakia

(4)

and their non-response was not pursued beyond one follow- up. Canada, Finland, Scotland, Sweden and Switzerland did not respond. In Scotland, nusinersen is reimbursed for SMA type 1 and from July 2019 it could be prescribed for SMA types 2/3 via the new ultra-orphan pathway. This agreement lasts for a period of up to 3 years while further evidence on effectiveness is generated, but no other details are available². Canada, Sweden and Finland have decentralised systems, where the provinces/hospitals/councils negotiate pricing and reimbursement and any OBMEA, but these agreements are confidential.

For Australia, France, Germany, Hungary, Norway and Slovenia, we were informed that nusinersen was reimbursed, often with strict inclusion criteria, but without an OBMEA.

According to the marketing authorisation holder, the Czech Republic does have a scheme that assesses effectiveness in children after 1 year of treatment and outcomes-based continuation criteria are applied, but no further details are available.

Templates returned from Austria, Portugal and Spain provided general responses about OBMEA construction and had few details for the specific treatment because the agreements are confidential. Austria made regional reimbursement decisions on nusinersen including for indications and any associated OBMEA, but it is known that one region collected motor milestones in the German SMArtCare registry³. For the remaining countries, templates were returned showing CED (population-based) schemes in Belgium, England and the Netherlands (Table 1). Responses from Bulgaria, Ireland, Italy and Lithuania showed individual- based OBMEAs used to determine eligibility, continuation and, in some cases, total budget caps that are intended to be used in pricing and reimbursement renegotiations (Table 2).

An initial response was received from Latvia that documented an individual-based scheme, but because of health system pressures, it has not been possible to validate the data summary. In Poland, it is unclear if the scheme proposed by the HTA body was implemented. These are shown in Table 2 in italic to enable comparisons to the individual- based schemes that were implemented, and for which there is validated information.

3.1.2 Tisagenlecleucel

In the data collection phase, it was determined from respondents or the marketing authorisation holder that at that point in time, Bulgaria, Estonia, Hungary, Ireland, Lat- via, Lithuania, Slovakia and Slovenia had not authorised/

reimbursed tisagenlecleucel and that Croatia, Cyprus, Den- mark, Greece, Iceland, Liechtenstein, Luxembourg, Malta,

New Zealand and Romania did not have OBMEAs. Con- tacts in the Czech Republic, Finland and Switzerland did not respond. For Portugal, a general response about the process was received indicating that any agreement would be made with INFARMED and the marketing authorisation holder, but that there was a preference for simple discounts.

Norway, Scotland and Sweden had reimbursed tisagenlecleucel through standard appraisal and reimbursement processes without need for an OBMEA. The Netherlands only uses population-based OBMEA for non-cancer OMPs, but can establish an individual-based agreement to ensure appropriate use. It did not use this for tisagenlecleucel, but gave reimbursement for acute lymphoblastic leukaemia only.

In Poland, there were originally applications for emergency access for a limited group of patients, then applications for reimbursement were made.

Jørgensen et al. [12] stated that in Germany during the initial 12-month free-pricing period, the marketing authorisation holder made arrangements with the health insurers, covering 60% of the eligible population, for an outcomes- based rebate for patients who died within a certain period.

After the early benefit assessment, the reimbursement mechanism has reverted to a simple confidential discount.

In Austria, for tisagenlecleucel, there was a national agreement on the reimbursed indication agreed by the national specialist group of haematologists⁴ and outcomes data are documented in the European Society for Blood and Marrow Transplantation. Reimbursement decisions (including any OBMEA) were agreed in regions and are confidential.

In Canada, CADTH recommended that tisagenlecleucel be provided via interprovincial agreements with clear eligibility criteria. It was recommended that standardised outcomes data be collected in a pan-Canadian registry to generate real-world evidence for consideration in future assessments to assess longer term effectiveness, safety and cost effectiveness⁵. No further details are published.

Templates were returned showing CED schemes in Aus- tralia, Belgium and England and an individual-based scheme in Italy. Publications and public reimbursement information described CED in France and an individual-based scheme in Spain. These are summarised in Table 3.

3.2 Country Comparisons Reimplementing OBMEAs Every jurisdiction has processes in place to develop commercial agreements/financial Managed Entry Agree- ments (MEA) within their pricing and reimbursement/

2 Nusinersen (Spinraza) (scottishmedicines.org.uk).

3 https:// www. smart care. de/ en/.

4 https:// www. oegho. at/ filea dmin/ Benut zer/ Aktue lles/ quali taets krite rien- car-t- zentr en- final_1. pdf.

5 Tisagenlecleucel (Kymriah) for Pediatric Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma | CADTH.ca.

(5)

Table 1 OBMEAs for nusinersen: coverage with evidence development Country Organisation Belgium National Ins

titute for Health and Disability Insur- ance (INAMI)

England National Institute for Health and Care Excellence (NICE)

The Netherlands Zorg Instituut (ZIN) P&R indication sought5q SMA5q SMA Types I, II, III and pre-symptomatic patients genetically destined to develop SMA5q SMA P&R date1/9/18July 20191. ≤ 9.5 years old 1/8/18 (fully reimbursed) 2. > 9.5 years old 1/1/20 (conditional) P&R special processConditional—Chapter IV of positive list (Joint negotiation in BENLUXA with Netherlands)Conditional on OBMEA and commercial agreement organised by NHS England and Improvement (NHSE&I)

OBMEA possible for OMPs (Joint negotiation in BENLUXA with Netherlands) 1. Ultra-rare, financial agreement until 1/21, with extension, “informal OBMEA” initiated after for- mal CED for other sub-population 2. Conditional reimbursement with legal OBMEA OBMEA population5q SMA not needing permanent ventilation 1. ≤ 9.5 years old – 1st symptoms before 6 mos, disease < 26 weeks – 1st symptoms 6–20 mos, disease < 94 mos – Pre-symptomatic babies with genetic diagnosis

and 2 or 3 SMN2 copies 2. > 9.5 y

ears old

5q SMA Types I–III and pre-symptomatic excluding – Permanent ventilation/ tracheostomy – Intrathecal injection not feasible – Had spinal fusion surgery – Severe contractures that prohibit measurement of motor milestones – Who gained ability to ambulate independently, but are no longer able to (except children who lost independent ambulation in prior 12 mos)

1. ≤ 9.5 years old—informal OBMEA – 1st symptoms before 6 months, disease < 26 weeks – 1st symptoms 6–20 mos, disease < 94 mos – Pre-symptomatic babies with genetic diagnosis and

2 or 3 SMN2 copies 2. > 9.5 y

ears old—Legal OBMEA Extensive exclusion criteria OBMEA Duration28 months (up to max of 3 years)5 years, with minimum of 3 years’ data collection1. Informal OBMEA planned to start—no end date 2. Legal OBMEA—7 years including HTA re-

assessment (290 pats r

ecruited in first 2 years) Purpose of OBMEAResolve uncertainties – Number pats treated in real life number pats treated by SMA type – Age at symptom appearance – Disease duration at onset of Rx – Real-life efficacy/safety: mortality, ventilation, performance, discontinuation reasons – Long-term efficacy/safety – Evidence in populations with no determined added value to date

To resolve clinical uncertainties in NICE appraisal with – Clinical data collection – PRO data collection – Resource utilisation data collection

1. In reimbursed population (≤ 9.5 years old), informal OBMEA to evaluate real-life effectiveness, determine appropriate use and cost effectiveness 2. For conditional coverage (> 9.5 years old), CED, legal OBMEA to collect enough evidence to determine if it is clinically and cost effective compared to no use (historic registry data) Use in re-appraisalRe-appraisal for P&R re-negotiations to convert to standard reimbursement or change in target population etc or to extend OBMEA

– 1 year review for a specific population (type III,

non-ambulant) – Reassessment in year 4 using at least 3 years of OBMEA data collection and any additional evidence from other sources. – Revised commercial agreement – Decision by year 5 to reimburse or not, no further OBMEA

1. Continuing process to refine start and stop criteria, collecting long-term follow up data and if it does not work as well as expected, reassessment can be initiated with potential to change advice to not reimburse or renegotiate price 2. Legal requirement for P&R re-negotiations

(6)

Table 1 (continued) Country Organisation Belgium National Ins

The Netherlands Zorg Instituut (ZIN) Stakeholders involved– INAMI Commission for Reimbursement proposed OBMEA to MAH, who accepted and developed OBMEA with MoH and INAMI MEA taskforce – Clinicians

– NICE can propose OBMEA according to clear criteria, developed in collaboration with MAH, NHSE&I, registry holder, clinicians and patient groups – Patient groups liaise with patients to explain OBMEA, feedback issues, input to data monitor-

ing discussions – Other members of the Managed Access Oversight Committee (MAOC) clinicians from 4 expert centres, academics responsible for development of PROM – National Clinical Panel assesses the patients included against the eligibility and continuation criteria on an annual basis and discuss other clinical issues that arise such as difficult cases requir- ing clinical judgement

– ZIN appraisal committee proposed both the informal and the legal OBMEAs to Minister of Health – Research group send application with research protocol to ZIN for review and approval this forms basis of legal agreement – Clinical expert centre, patient group, health insurers, bureau of university hospitals, pharmacists (and for legal OBMEA MoH) Treatment stopping criteriaPermanent ventilation– Permanent ventilation (≥ 16 h/day for 21 consecutive days in the absence of acute reversible infec- tion) or requirement of insertion of permanent tracheostomy. – Total worsening in outcome score corroborated by two consecutive measurements. A scaled equiva- lent of these losses would apply if a domain was unmeasurable/not suitable: > 2 points on horizontal kick or 1 point on other HINE scores excluding voluntary grasp > 4 points on the CHOP INTEND scale > 3 points on the Revised Hammersmith scale – Inability to regain ambulation within 12 months of

nusinersen initiation – Inability t

o give intrathecal administration because of spinal fusion surgery

1. 9.5 years old reimbursed population, informal OBMEA—not known yet, will be evaluated in the informal OBMEA 2. 9.5 years old CED, legal OBMEA– not stipulated, but important to establish if reimbursement is agreed after OBMEA Data sources– INAMI and Insurance Funds have established a bespoke registry with healthdata.be that links into the internationally coordinated SMA registry Data from the registry will be combined with INAMI reimbursement data – MAH can also collect data through other routes

– Completion of ongoing trials – SMA REACH registry (organised by leading children’s hospital) – NHS Blueteq (System for high-cost drugs) – PROMs being developed

1. Dutch registry 2. Dutch registry developed for use by clinicians in the expert centre and data will be compared with historical Dutch cohort

(7)

The Netherlands Zorg Instituut (ZIN) Data collectedTo resolve stated uncertainties, details confidential– Nusinersen (use, first dose, dose, combination therapy, parental perceived benefit) – Survival, need for ventilation (+ respiratory events) – Motor function (various measures)

– Scoliosis – Fractures – Nasogastric tube, gastrostomy placement – For each group a “primary” endpoint is defined in the DCA and many other endpoints as well

1. ≤ 9.5 years old, reimbursed population, informal

OBMEA (data collection still under development) 2. > 9.5 years old, CED, legal OBMEA A lot of data to assess clinical and cost effectiveness with specific research questions compared to historical control. Primary endpoints: If HFMSE score ≥ 5, decrease in HFMSE over 4 years follow-up. MCID—75% reduction in the average decrease compared to the historical cohort. (HFMSE decreases by an average of 0.8 points per year in historical cohort, so there is a clinically relevant difference if the HFMSE score decreases by an average of ≤ 0.2 points per year). IF HFMSE < 5, RULM is the primary outcome measure. Secondary efficacy measures: RULM, EQ-5D, SF-36, PedsQoL, SMA-FRS, fatigue (measured with the ES9HPT, ESBBT and ESWT), Safety: side effects, serious side effects Economics: budget impact and cost effectiveness. Data Analysis Plan?Developed by MAH1. Expert centre 2. Research group from expert centre Frequency of data collectionAnnually, with an initial delay: so 2020, 2021, 2022Twice per year (at least 4 months apart) to coincide with 6-monthly follow-ups or 4-monthly admin- istrations

1. ≤ 9.5 years old, informal OBMEA—not known yet 2. > 9.5 years old, legal OBMEA—every 3–6 months Interim data reviewsNoneSMA REACH (registry) 6-monthly – Summary reports to MAOC to monitor data completeness and case ascertainment. – Pseudo-anonymised individual reports to Clinical Panel to monitor eligibility and stopping rules MAH provides annual summary data At end of year 1 provide evidence submission to NICE re non-ambulant type III

1. Aggregated public data reported in ZIN annual report “monitoring orphan drugs in practice” 2. Group meets 6-monthly to review status of research—no. of patients treated, no. on waiting list, no. stopped treatment etc and reported in annual report about use of OMPs Data quality processNo– Mandatory fields to be completed – Registry holder undertakes site monitoring of data entry and remote monitoring of completeness. – MAOC checks case ascertainment figures from another NHS data source (Blueteq)

Organised by the research centre

(8)

commissioning process, many of which have a clear legal underpinning. These commercial agreements are highly confidential and generally only involve the marketing authorisation holder and the payer/Ministry of Health and for our case studies, range from simple discounts to budget caps (Belgium, Bulgaria, Latvia [unvalidated], Lithuania, Spain).

Despite the confidentiality of these commercial agreements, public information was available for many jurisdictions to populate our OBMEA templates for the two case studies. As shown in Tables 1, 2, and 3, information was available about the rationale and design of the OBMEA in different countries covering topics that elucidate the purpose of the OBMEA, population given access, duration of agreement, stakeholder involvement, data to be collected and reporting mechanisms. These elements are presented in the following sections with augmentation of intelligence from the HTA expert workshops.

3.2.1 Establishing the OBMEA

Some countries have standing committees that oversee the establishment of all OBMEAs (such as Belgium) inviting in clinical/appraisal experts relevant to the treatment. In Eng- land, the case studies come from two separate programmes within NICE, the Cancer Drugs Fund and the HST programme. They had different processes for the establishment of OBMEAs, thus the form of data collection agreements is slightly different for the case studies (but rationalisation of these OBMEA processes is underway for the future).

Outcomes-based managed entry agreements are sometimes limited to specific groups of medicines such as (high- cost) OMPs or those with conditional or exceptional marketing authorisations, nusinersen was considered via this route in The Netherlands. In some countries, OBMEAs are mandated for all medicines in a certain category, for example, in Italy those with a full innovation status must have a national registry that at least determines appropriate use (guiding eligibility for treatment and continuation criteria), as was the case for nusinersen, whereas tisagenlecleucel was the first product to undergo the “Payment at Results” OBMEAs in AIFA. In other countries, the use of an OBMEA for nusinersen and tisagenlecleucel was considered on a case-by-case basis to support appropriate use in individual patients and/or data collection to resolve clinical (and economic) uncertainties.

The OBMEAs for nusinersen were initiated between 2017 and 2020 and as shown by Whittal et al. [13] more evidence from studies in different sub-populations, clinical study follow-ups and real-world effectiveness might have been available for the later reimbursement decisions. This could have potentially resolved some uncertainties and impacted their need for OBMEA. For tisagenlecleucel, decisions were made at very similar times between January and August 2019.

The Netherlands Zorg Instituut (ZIN) Funder for data collectionINAMI for the new SMA registry MAHMAH1. No standard system for informal OBMEA 2. MAH Funder for data processingMAHMAH and SMA REACH1. No standard system for informal OBMEA 2. MAH CED Coverage with Evidence Development, CHOP INTEND Children`s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, ES9HPT Endurance Shuttle Nine Hole Peg Test, ESBBT Endurance Shuttle Box and Block Test, ESWT Endurance Shuttle Walk Test, FRS Functional Rating Scale, HFMSE Hammersmith Functional Motor Scale Expanded, HINE Hammer- smith Infant Neurological Examination, INAMI National Institute for Health and Disability Insurance, MAH Marketing Authorisation Holder, MAOC Managed Access Oversight Committee, mos months, MoH Ministry of Health, MCID minimum clinically important difference, NHIF National Health Insurance Fund, NHSE&I NHS England and Improvement, NICE National Insti- tute for Health and Care Excellence, OBMEA Outcomes-Based Managed Entry Agreement, OMP orphan medicinal product, P&R pricing and reimbursement, PROM patient-reported outcome measure, Rx treatment, RULM revised upper limb module, SMA spinal muscular atrophy, ZIN Zorg Instituut

(9)

Table 2 OBMEAs for nusinersen: individual agreements Country Organisation (respondent if not from organisation)

Bulgaria National Health Insurance Fund (TB, Founding President of National Council on Prices and Reimbursement of Medicinal Products)

Ireland Health Service Executive (HSE) (AOL, NCPE)

Italy Italian Medicines Agency (AIFA) (EX, formerly AIFA) P&R indication sought5q SMAChildren aged < 18 years with genetically confirmed SMA types I, II or III

5q SMA types I–III No ag

e limitation P&R date29/9/19, inclusion in NHIF list 1/1/20December 2017 following HTA not deemed to be cost effective and further pricing negotiations28/9/17 P&R special processPrescription for individual patients according to protocol approved by special commission in NHIFUltra-rare Conditional reimbursement according to protocol published by MoH

Fund for innovative drugs achieved “full” innovation score valid for 3 years (28/09/2017–17/09/2020), with P&R contract re-negotiations annually http:// www. aifa. gov. it/ sites/ defau lt/ files/6- Spinr aza_ v1.0. pdf OBMEA populationChildren with 5q SMA aged < 18 years excluding those with - Anamnesis of peripheral or CNS disease - Severe scoliosis - Coagulation disorders - Hypersensitivity with manifestations of severe anaphylactic reactions to active substance or excipients - Those in a clinical trial for SMA Patients cannot receive treatment with other drugs paid by NHIF for the same indication, which are not included in the protocol

National Drugs Management Protocol states: Children aged < 18 years with genetically confirmed SMA types I, II or III excluding those with contraindications and - Patients with other life-limiting conditions

- SMA type 0 - Clinical and g

enetic diagnosis of SMA not fulfilled - Current participation in a clinical trial with an investigational gene therapy for SMA - Comorbidities that might preclude lumbar punc- ture Patients prioritised on the basis of clinical need and the potential for treatment benefit

Genetically confirmed 5q SMA types I–III with no more than 4 copies of SMN2 gene. SMN1 for naive patients OBMEA duration3 years28 months? Planned to start in August 2019, but some delays in execution

1 year and reviewed annually, often beyond innovation status, for many years 1st PR negotiation 28/09/17 https:// www. aifa. gov. it/ sites/ defau lt/ files/ Deter mina_ 1611- 2017_ Spinr aza. pdf PR re-negotiation 29/9/18 https:// www. gazze ttauffi cia le. it/ eli/ id/ 2018/ 09/ 27/ 18A06 132/ sg Purpose of OBMEAObligatory requirement for some form of MEA as condition for positive drug list This OBMEA to ensure appropriate use and treatment discontinuation

Resolve uncertainties about long-term benefit by ensuring appropriate use including treatment discontinuation

Manage clinical uncertainty by ensuring appropriate use including treatment discontinuation Use in re-appraisal(OB)MEAs valid for 3 years until reimbursement re-negotiationAs defined in protocol, originally planned for review in November 2021Part of the annual review of P&R contract

(10)

Table 2 (continued) Country Organisation (respondent if not from organisation)

Bulgaria National Health Insurance Fund (TB, Founding President of National Council on Prices and Reimbursement of Medicinal Products)

Ireland Health Service Executive (HSE) (AOL, NCPE)

Italy Italian Medicines Agency (AIFA) (EX, formerly AIFA) Stakeholders involvedNHIF and MAH- Healthcare payer: primary care eligibility and reimbursement service - HSE medicines management programme (HSE MMP) to review individual applications for treatment against protocol (developed with clinicians)

- AIFA establishes registry for use by hospitals, can access anonymised data to produce reports - MAH funds registry - Regions: authorise prescribing centres - Health managers authorise clinicians and pharmacists - Clinicians/pharmacists: dispensing and access depends on entries into the registry for initiating and continuing treatment Treatment stopping criteriaAssessment of performance status according to HFMSE, CHOP INTEND and HINE for SMA type 1 and RULM for SMA type 2 and re-evaluation of exclusion criteriaa

Differentiated for SMA types, based on motor/ mobility scales, respiratory and patient/clinician viewsbNone Data sourcesHospitalsHospital clinicians (paper based), submitted to HSE-MMP for reviewDrug-specific national web-based registry Data collectedConfidentialAs outlined in protocolb: - Baseline patient characteristics - Treatment information - Outcomes at 12 months to determine treatment continuation, different for each SMA type

Baseline patient characteristics Inclusion criteria: Patient with a genetically confirmed diagnosis of SMA 5q (mutations in the SMN1 gene), alleged SMA phenotype (types 1, 2,

3a or 3b) For patients diagnosed wit

h SMA type 2, the forced vital capacity measurement to be collected Tests: CHOP INTEND, Motor milestones HINE, or

HFMSE Information about whether patient has already been treated and appears in early access registry (as for all the AIFA registries) Date of nusinersen administration and dose First assessments after the loading dose and each four months of treatment - Clinician overall assessment - % change in score (CHOP INTEND, motor mile-

stones HINE or HFMSE) - Disease pr

ogression, patient death, drug toxicity Treatment continuation decision End of treatment, date, reason, end-points (Electronic Supplementary Material) Data analysis planNHIFHSE-MMPAIFA https:// www. aifa. gov. it/ en/-/ attiv azione- del- regis tro- spinr aza- 12- 12- 2017-